There is a consensus among most investigators that immunological factors can induce and may be involved in the etiology and pathogenesis of psychiatric disorders. However, there is controversy about which elements of the immune system play the most significant role. One such debate centers on the role of T helper (TH) cell subsets, and the cytokines they produce. Activated TH cells are implicated in psychopathological outcomes that are linked with aberrations in the mesocorticolimbic and -striatal systems and repetitive behaviors (notably psychosis, schizophrenic-like behavior, cognitive deficits). However, a systematic analysis of the neurobehavioral consequences of TH cell subsets is lacking. We have developed TH1 and TH2 cell lines that are responsive to endogenous viral-encoded superantigens that are expressed on the surface of B lymphoma cells in SJL/J mice. We have preliminary evidence that adoptive transfer of TH1 cells into syngeneic recipients induces a rapid increase in the incidence and intensity of stereotyped behavior. This implies that TH1 cells influence neuronal activity in the mesostriatal system. Paralleling this finding, (a) adoptive transfer of activated T cells induces a pronounced behavioral activation that is characterized by an increase in stereotypical motor activity, and (b) a relatively large percentage of systemically applied lymphocytes are rapidly transported across the blood-brain barrier (BBB). Interestingly, there is a temporal congruence between the time of peak lymphocyte entry into the brain and the time of peak increases in stereotyped behavior after TH1 cell administration. This observation strongly supports the hypothesis that lymphocyte entry into the brain increases vulnerability to psychopathological outcome since the passage of immune cells across the BBB closely correlates with disease activity in some neurological diseases (e.g., MS and its animal model, EAE). This R21 proposal using mouse TH cell lines injected into syngeneic recipients will permit a detailed analysis of the neurobehavioral consequences of TH cells. We propose to characterize the effects of TH1 and TH2 cells on stereotyped behavior, examine the role of other behavior thereby generating a comprehensive behavioral profile, and determining if the behavioral changes are related to the ability of TH cells to be transported across the BBB, particularly into mesostriatal structures, and to altered neuronal activity in these structures.